Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

doi:10.1016/j.cytogfr.2005.01.004

Cytokine & Growth Factor Reviews

Volume 16, Issue 2, April 2005, Pages 159-178

https://doi.org/10.1016/j.cytogfr.2005.01.004 Get rights and content

Abstract

Fibroblast growth factors (FGFs) are a family of heparin-binding growth factors. FGFs exert their pro-angiogenic activity by interacting with various endothelial cell surface receptors, including tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins. Their activity is modulated by a variety of free and extracellular matrix-associated molecules. Also, the cross-talk among FGFs, vascular endothelial growth factors (VEGFs), and inflammatory cytokines/chemokines may play a role in the modulation of blood vessel growth in different pathological conditions, including cancer. Indeed, several experimental evidences point to a role for FGFs in tumor growth and angiogenesis. This review will focus on the relevance of the FGF/FGF receptor system in adult angiogenesis and its contribution to tumor vascularization.

Introduction

Angiogenesis, the process of new blood vessel formation from pre-existing ones, plays a key role in various physiological and pathological conditions, including embryonic development, wound repair, inflammation, and tumor growth [1]. The local, uncontrolled release of angiogenic growth factors and/or alterations of the production of natural angiogenic inhibitors, with a consequent alteration of the angiogenic balance [2], are responsible for the uncontrolled endothelial cell proliferation that takes place during tumor neovascularization and in angiogenesis-dependent diseases [3].

Angiogenesis is a multi-step process that begins with the degradation of the basement membrane by activated endothelial cells that will migrate and proliferate, leading to the formation of solid endothelial cell sprouts into the stromal space. Then, vascular loops are formed and capillary tubes develop with formation of tight junctions and deposition of new basement membrane [4].

Numerous inducers of angiogenesis have been identified, including the members of the vascular endothelial growth factor (VEGF) family, angiopoietins, transforming growth factor-α and -β (TGF-α and -β), platelet-derived growth factor (PDGF), tumor necrosis factor-α (TNF-α), interleukins, chemokines, and the members of the fibroblast growth factor (FGF) family.

Historically, a tumor angiogenic factor (TAF) was first isolated in 1971 from rat Walker 256 carcinoma [5]. TAF had a molecular weight of about 10 kDa and consisted of 25% RNA, 10% proteins, and 58% carbohydrates, plus a possible lipid fraction. The 1980s saw for the first time the purification to homogeneity of pro-angiogenic proteins, the breakthrough coming as a result of the observation that endothelial cell growth factors showed a marked affinity for heparin [6], [7]. This led to the identification, purification, and sequencing of the two prototypic heparin-binding angiogenic growth factors FGF1 and FGF2. Since then, 22 structurally-related members of the FGF family have been identified [8]. FGFs are pleiotropic factors acting on different cell types, including endothelial cells, following interaction with heparan-sulfate proteoglycans (HSPGs) and tyrosine kinase FGF receptors (FGFRs). To date, more than 1200 PubMed-referenced papers related to FGFs and FGFRs in endothelial cells and during neovascularization have been published. This review will focus on the role of the FGF/FGFR system in angiogenesis.

Section snippets

Pro-angiogenic activity of FGFs

As stated above, FGFs exert their biological activities by binding to high affinity tyrosine kinase FGFRs on the surface of target cells. In vitro, endothelial cells of different origin express FGFR1 [9], [10] and, under some circumstances, FGFR2 [11] whereas the expression of FGFR3 or FGFR4 has never been reported in endothelium.

Only a limited number among the 22 members of the FGF family have been investigated for their angiogenic potential in vitro and in vivo, the bulk of experimental data

FGF interaction with endothelial cell surface, extracellular matrix, and free molecules

As stated above, FGFs interact with signaling FGFRs expressed on the endothelial cell surface. However, various other binding partners can affect the biological activity and angiogenic potential of FGFs (Fig. 2). These molecules can interact with FGFs in the extracellular environment, thus modulating their bioavailability, stability, local concentration, interaction with endothelial receptors, and intracellular fate. The complexity of this network of interactions is manifold: (i) FGF-binding

Experimental tumors

Various tumor cell lines express FGF2 [174], [175] and the appearance of an angiogenic phenotype correlates with the export of FGF2 during the development of fibrosarcoma in a transgenic mouse model [176]. Antisense cDNAs for FGF2 and FGFR1 inhibit neovascularization and growth of human melanomas in nude mice [177]. Also, the anti-angiogenic activity of IFN-α/β appears to be related, at least in part, to the capacity to down-regulate FGF2 expression [178]. These data suggest that FGF2

FGF-dependent angiogenesis and inflammation

Inflammation is the response of a vascularized tissue to sub-lethal injury, designed to destroy or inactivate invading pathogens, remove waste and debris, and permit restoration of normal function, either through resolution or repair.

Inflammation may promote FGF-dependent angiogenesis (Fig. 4). Inflammatory cells, including mononuclear phagocytes [204], [205], CD4⁺ and CD8⁺ T lymphocytes [206], [207], and mast cells [208] can express FGF2. Moreover, osmotic shock and shear stress induce the

FGFs and therapeutic angiogenesis

Therapeutic angiogenesis represents a possible approach to the treatment of severe ischemic diseases in patients with coronary (CAD) or peripheral (PAD) artery injury. Aim of this therapy is to restore and maintain tissue perfusion by increasing the number of collateral blood vessels within the ischemic territories following the delivery of specific angiogenic growth factors. Different delivery methods, including intravenous, intracoronary, intramyocardial and intrapericardial routes, are

Acknowledgements

Limitations of space preclude extensive citation of the literature; we apologize with those whose work is not mentioned herein. This work was supported by grants from AIRC, MIUR (Centro di Eccellenza “IDET”, Firb 2001, Cofin 2002, and Cofin 2004), ISS (Oncotechnological Program), and Fondazione Berlucchi to MP and from MIUR (Cofin 2003) and ISS (AIDS Project) to MR.

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Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Abstract

Introduction

Section snippets

Pro-angiogenic activity of FGFs

FGF interaction with endothelial cell surface, extracellular matrix, and free molecules

Experimental tumors

FGF-dependent angiogenesis and inflammation

FGFs and therapeutic angiogenesis

Acknowledgements

Cell

Trends Genet

Trends Mol Med

Trends Pharmacol Sci

Trends Pharmacol Sci

Cell

Cell

J Biol Chem

Am J Pathol

Exp Cell Res

FEBS Lett

J Biol Chem

Exp Cell Res

Int J Biochem Cell Biol

J Invest Dermatol

Exp Cell Res

J Biol Chem

Mod Pathol

J Biol Chem

Placenta

Acta Haematol

J Biol Chem

Am J Pathol

Am J Pathol

Angiogenesis in cancer and other diseases

Nature

Angiogenesis in cancer, vascular, rheumatoid and other disease

Nat Med

Mechanisms of angiogenesis and arteriogenesis

Nat Med

Isolation of a tumor factor responsible or angiogenesis

J Exp Med

Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor

Science

Heparin binds endothelial cell growth factor, the principal endothelial cell mitogen in bovine brain

Science

Basic fibroblast growth factor-induced angiogenic phenotype in mouse endothelium. A study of aortic and microvascular endothelial cell lines

Arterioscler Thromb Vasc Biol

Paracrine and autocrine effects of fibroblast growth factor-4 in endothelial cells

Oncogene

Endothelial cell culture: beginnings of modern vascular biology

J Clin Invest

Heterogeneity of endothelial cells. Specific markers

Arterioscler Thromb Vasc Biol

Endothelial cell diversity revealed by global expression profiling

Proc Natl Acad Sci USA

FGF-8b increases angiogenic capacity and tumor growth of androgen-regulated S115 breast cancer cells

Oncogene

Basic fibroblast growth factor requires a long-lasting activation of protein kinase C to induce cell proliferation in transformed fetal bovine aortic endothelial cells

Cell Regul

Different tyrosine autophosphorylation requirements in fibroblast growth factor receptor-1 mediate urokinase-type plasminogen activator induction and mitogenesis

Mol Biol Cell

Nonenzymatic interactions between proteinases and the cell surface: novel roles in normal and malignant cell physiology

Adv Cancer Res

Induction of plasminogen activator inhibitor-1 in endothelial cells by basic fibroblast growth factor and its modulation by fibric acid

Arterioscler Thromb Vasc Biol

Plasminogen activator inhibitor-1 is induced in migrating endothelial cells

J Cell Physiol

Human endothelial cells are chemotactic to endothelial cell growth factor and heparin

J Cell Biol

Chemotaxis of human microvessel endothelial cells in response to acidic fibroblast growth factor

Lab Invest

Keratinocyte growth factor induces angiogenesis and protects endothelial barrier function

J Cell Sci

Fibroblast growth factor receptor-1 mediates chemotaxis independently of direct SH2-domain protein binding

Oncogene

Modulation of microvascular growth and morphogenesis by reconstituted basement membrane gel in three-dimensional cultures of rat aorta: a comparative study of angiogenesis in matrigel, collagen, fibrin, and plasma clot

In Vitro Cell Dev Biol

In vitro rapid organization of endothelial cells into capillary-like networks is promoted by collagen matrices

J Cell Biol